The influence of the spinal cord on gastrointestinal function has only recently been recognized. Drugs can influence the gut at 4 different levels: the neurons of the enteric nervous system, the smooth muscle of the gut, the brain and as only recently shown, the spinal cord. The understanding of the relative contributions of the brain and spinal cord to the central modulation of gastrointestinal function is potentially of major importance in clinical practice. Preliminary data have indicated that opioids that effectively alter gut motility at the level of the cord are not necessarily effective at the level of the brain. The aim of this proposal is to elucidate the opioid mechanisms involved in control of gut function at the level of the spinal cord and within the brain, and the relative importance of these central structures. The studies will be on the gastrointestinal pharmacology of selective opioid receptor agonists and specific receptor antagonists. The approach involves 3 tactics: (1) the concurrent administration of threshold and subthreshold doses at both the brain and cord levels in order to determine possible additive or multiplicative effects, i.e., site-site interaction; data from these experiments will be subjected to isobolographic analysis in order to reveal the nature of the brain-cord interaction; (2) administration of agonists and antagonists by the same, or different systemic, i.c.v. or i.t. routes; and (3) the use of tolerance and cross-tolerance techniques to functionally eliminate the participation of a particular site or receptor subclass from producing the effect. The endpoints chosen focus on gastroin-testinal transit in the mouse for the first half of the proposed funding period and shift to the study of gastric emptying, small and large intestinal transit and gastric and intestinal motility in the rat as the understanding of brain-cord interaction is achieved. Additionally, animal models will include normal and spinally-transected animals so that the neural and cerebrospinal fluid connections between the brain and cord can be interrupted. The presence of high concentrations of enkephalins within the brain, the spinal cord and the gut, suggests that an understanding of the relative contributions of the brain and spinal cord and the specific opioid receptor mechanisms involved in the opioid modulation of gut function will provide new insights into the CNS-gut interface.